The proposed research is designed to determine the mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is anorectic and toxic. The first hypothesis to be tested is that TCDD is anorectic because of its effects on serum thyroxine levels. One of the first effects of TCDD is to decrease serum thyroxine levels. The response to low serum thyroxine levels is increased thyrotropin releasing hormone (TRH) in the hypothalamus and thyroid stimulating hormone (TSH) in the pituitary. This would normally restore circulating levels of thyroxine. Unfortunately, excess TRH in the hypothalamus is anorectic. The second hypothesis is that TCDD is toxic to many tissues because it interferes with vitamin A dependent protein glycosylation. TCDD causes the release of vitamin A stored in the liver, however, the extrahepatic tissues still appear to develop a vitamin A deficiency in the face of increased serum levels of vitamin A. The problem could be a deficiency in the absorption of vitamin A from the serum or inability to utilize the vitamin A in the extrahepatic tissues. Since vitamin A is required for protein glycosylation we propose that this process is deficient in TCDD-treated animals. This could be fatal because of the many requirements for protein glycosylation, such as cell surface receptors, hormones, etc. We propose to study the effects of TCDD on the intermediates and the enzymes involved in vitamin A dependent protein glycosylation.